Nuclear Function of Smad7 Promotes Myogenesis

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2009 Dec 10

PMID 19995910

Citations 26

Authors

Tetsuaki Miyake

Nezeka S Alli

John C McDermott

Affiliations

Soon will be listed here.

Abstract

In the "canonical" view of transforming growth factor beta (TGF-beta) signaling, Smad7 plays an inhibitory role. While Smad7 represses Smad3 activation by TGF-beta, it does not reverse the inhibitory effect of TGF-beta on myogenesis, suggesting a different function in myogenic cells. We previously reported a promyogenic role of Smad7 mediated by an interaction with MyoD. Based on this association, we hypothesized a possible nuclear function of Smad7 independent of its role at the level of the receptor. We therefore engineered a chimera of Smad7 with a nuclear localization signal (NLS), which serves to prevent and therefore bypass binding to the TGF-beta receptor while concomitantly constitutively localizing Smad7 to the nucleus. This Smad7-NLS did not repress Smad3 activation by TGF-beta but did retain its ability to enhance myogenic gene activation and phenotypic myogenesis, indicating that the nuclear, receptor-independent function of Smad7 is sufficient to promote myogenesis. Furthermore, Smad7 physically interacts with MyoD and antagonizes the repressive effects of active MEK on MyoD. Reporter and myogenic conversion assays indicate a pivotal regulation of MyoD transcriptional properties by the balance between Smad7 and active MEK. Thus, Smad7 has a nuclear coactivator function that is independent of TGF-beta signaling and necessary to promote myogenic differentiation.

Citing Articles

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References

Massague J, Seoane J, Wotton D . Smad transcription factors. Genes Dev. 2005; 19(23):2783-810. DOI: 10.1101/gad.1350705. View

De Angelis L, Zhao J, Andreucci J, Olson E, Cossu G, McDermott J . Regulation of vertebrate myotome development by the p38 MAP kinase-MEF2 signaling pathway. Dev Biol. 2005; 283(1):171-9. DOI: 10.1016/j.ydbio.2005.04.009. View

Jo C, Kim H, Jo I, Choi I, Jung S, Kim J . Leukemia inhibitory factor blocks early differentiation of skeletal muscle cells by activating ERK. Biochim Biophys Acta. 2005; 1743(3):187-97. DOI: 10.1016/j.bbamcr.2004.11.002. View

Song A, Wang Q, Goebl M, Harrington M . Phosphorylation of nuclear MyoD is required for its rapid degradation. Mol Cell Biol. 1998; 18(9):4994-9. PMC: 109084. DOI: 10.1128/MCB.18.9.4994. View

Hanaoka K, Hayasaka M, Esumi E, Li S, Nonaka I, Nabeshima Y . Myogenin gene disruption results in perinatal lethality because of severe muscle defect. Nature. 1993; 364(6437):532-5. DOI: 10.1038/364532a0. View

Engert J, BERGLUND E, Rosenthal N . Proliferation precedes differentiation in IGF-I-stimulated myogenesis. J Cell Biol. 1996; 135(2):431-40. PMC: 2121039. DOI: 10.1083/jcb.135.2.431. View

Maves L, Waskiewicz A, Paul B, Cao Y, Tyler A, Moens C . Pbx homeodomain proteins direct Myod activity to promote fast-muscle differentiation. Development. 2007; 134(18):3371-82. DOI: 10.1242/dev.003905. View

Grobet L, Martin L, Poncelet D, Pirottin D, Brouwers B, Riquet J . A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet. 1997; 17(1):71-4. DOI: 10.1038/ng0997-71. View

Perry R, Parker M, Rudnicki M . Activated MEK1 binds the nuclear MyoD transcriptional complex to repress transactivation. Mol Cell. 2001; 8(2):291-301. DOI: 10.1016/s1097-2765(01)00302-1. View

10.

Hayashi H, Abdollah S, Qiu Y, Cai J, Xu Y, Grinnell B . The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell. 1997; 89(7):1165-73. DOI: 10.1016/s0092-8674(00)80303-7. View

11.

Miska E, Karlsson C, Langley E, Nielsen S, Pines J, Kouzarides T . HDAC4 deacetylase associates with and represses the MEF2 transcription factor. EMBO J. 1999; 18(18):5099-107. PMC: 1171580. DOI: 10.1093/emboj/18.18.5099. View

12.

Nakao A, Afrakhte M, Moren A, Nakayama T, Christian J, Heuchel R . Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature. 1997; 389(6651):631-5. DOI: 10.1038/39369. View

13.

Levy L, Hill C . Smad4 dependency defines two classes of transforming growth factor {beta} (TGF-{beta}) target genes and distinguishes TGF-{beta}-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses. Mol Cell Biol. 2005; 25(18):8108-25. PMC: 1234333. DOI: 10.1128/MCB.25.18.8108-8125.2005. View

14.

Amthor H, Huang R, McKinnell I, Christ B, Kambadur R, Sharma M . The regulation and action of myostatin as a negative regulator of muscle development during avian embryogenesis. Dev Biol. 2002; 251(2):241-57. DOI: 10.1006/dbio.2002.0812. View

15.

Donoviel D, Shield M, Buskin J, Haugen H, Clegg C, Hauschka S . Analysis of muscle creatine kinase gene regulatory elements in skeletal and cardiac muscles of transgenic mice. Mol Cell Biol. 1996; 16(4):1649-58. PMC: 231151. DOI: 10.1128/MCB.16.4.1649. View

16.

Ornatsky O, Cox D, Tangirala P, Andreucci J, Quinn Z, Wrana J . Post-translational control of the MEF2A transcriptional regulatory protein. Nucleic Acids Res. 1999; 27(13):2646-54. PMC: 148473. DOI: 10.1093/nar/27.13.2646. View

17.

Schmierer B, Hill C . TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol. 2007; 8(12):970-82. DOI: 10.1038/nrm2297. View

18.

Olwin B, Hauschka S . Cell surface fibroblast growth factor and epidermal growth factor receptors are permanently lost during skeletal muscle terminal differentiation in culture. J Cell Biol. 1988; 107(2):761-9. PMC: 2115215. DOI: 10.1083/jcb.107.2.761. View

19.

Yang C, Ornatsky O, McDermott J, Cruz T, Prody C . Interaction of myocyte enhancer factor 2 (MEF2) with a mitogen-activated protein kinase, ERK5/BMK1. Nucleic Acids Res. 1998; 26(20):4771-7. PMC: 147902. DOI: 10.1093/nar/26.20.4771. View

20.

McPherron A, Lee S . Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci U S A. 1997; 94(23):12457-61. PMC: 24998. DOI: 10.1073/pnas.94.23.12457. View